CN109369647B - A kind of synthetic method of fused ring [1,2-a]indole compound and 2,3-disubstituted indole compound - Google Patents

Abstract

The invention discloses a method for synthesizing fused ring [1,2-a]indole compounds and 2,3-disubstituted indole compounds. The specific method of the present invention is to add catalyst D, enaminone E and alkali into an organic solvent to react, and through separation and purification, a fused ring [1,2-a]indole compound F is obtained. The catalyst required by the method is cheap copper complex or palladium acetate without ligand, the catalyst dosage is low, the substrate universality is good, and the synthesis of 2,3-disubstituted indole can be realized by adjusting the type of base. The prepared indole compounds can be widely used in the fields of medicinal chemistry and organic synthesis.

Description

A condensed ring [1,2-a]indole compound and 2,3-disubstituted indole compound method of synthesis

technical field

The invention relates to a method for synthesizing fused ring [1,2-a]indole compounds and 2,3-disubstituted indole compounds, belonging to the field of organic synthesis.

Background technique

Condensed [1,2-a]indole derivatives are widely found in nature and are the core skeleton of many natural products with important biological activity and medicinal value, as well as drug molecules. [a) J. Pharmacol. Exp. Ther. 1993, 265, 752. b) Chem. Pharm. Bull. 1994, 42, 2546. c) Chem. Pharm. Bull. 1995, 43, 1346]. Fused ring [1,2-a]indole derivatives are important precursors for the synthesis of these active molecules, such as natural product Gonimitine, drug molecule FK-1052 and so on.

At present, the preparation methods of such fused-ring [1,2-a]indole derivatives mainly include: (1) Fischer indole synthesis method, firstly by phenylhydrazine and 2-substituted 1,3-cyclohexanediol Ketones generate phenylhydrazone derivatives, which undergo a [3,3] rearrangement, and then remove a molecule of ammonia to prepare [1) Arch.Pharm.1982, 315, 388.2) Tetrahedron 1992, 48, 5991.3) Tetrahedron 1983, 39, 3657.4) Heterocycles 2017,95,1245], this method is mainly limited by the electrical properties of phenylhydrazine, and can only synthesize electron-rich and less sterically hindered fused ring [1,2-a]indole derivatives; ( 2) Carbon-nitrogen/carbon-carbon coupling reactions involving transition metals to prepare [1) Org. Lett. 2000, 2, 1109.; 2) Org. Lett. 2006, 8, 3573; 3) Adv. Synth. Catal. 2010, 352, 2667.4) Angew. Chem. Int. Ed. 2014, 53, 785; 5) Chem. Eur. J. 2014, 20, 12768.6) Angew. Chem. Int. Ed. 2017, 56, 2754.]. The main problems of these methods are relatively high catalyst dosage, relatively expensive ligands, or inconvenient source of raw materials. Therefore, it is necessary to develop a high-efficiency, convenient raw material source, less catalyst dosage, and good economical synthesis method.

SUMMARY OF THE INVENTION

In order to solve the problems existing in the prior art, the present invention uses cheap and readily available commodities as raw materials, and under the action of very cheap copper catalysts or very low consumption palladium catalysts, constructs fused ring [1,2-a]indole and based on this method, a synthetic method of 2,3-disubstituted indole compounds was constructed. The conditions are relatively simple, the post-processing is convenient, and the industrial prospect is good.

The technical scheme of the present invention is as follows:

In a first aspect, a method for preparing a fused ring [1,2-a] indole compound is provided, wherein the fused ring [1,2-a] indole compound has the formula shown by F in the formula (A). The specific steps are as follows: in an organic solvent, adding catalyst D, substrate enaminone E and base to react at room temperature, and then separating and purifying to obtain a condensed ring [1,2-a]indole compound, reacting The process is shown in equation (A):

Equation (A):

Described raw material enaminone E has the structure shown in E in equation (A);

Wherein, R ¹ is alkyl, cycloalkyl, heteroatom-containing alkyl, aryl, heteroaryl or fluorine; R ² , R ³ , R ⁴ , R ⁵ are each independently, optionally from the following structures: hydrogen Atom, alkyl, cycloalkyl, heteroatom-containing alkyl, fluorine, chlorine, bromoalkyl substituted acyl; cyano; nitro; ester; alkyl or aryl substituted amine; alkyl or aryl substituted Oxygen; Substituted silicon group; R ² and R ³ , R ³ and R ⁴ , R ⁴ and R ⁵ form a ring or not;

Wherein, R ⁶ , R ⁷ , R ⁸ , R ⁹ are optionally selected from the following structures: hydrogen atom, alkyl group, cycloalkyl group, heteroatom-containing alkyl group, fluorine, chlorine, etc.;

Wherein, X ₁ , X ₂ , X ₃ , and X ₄ are optionally selected from C or N, and are one of the following combinations: X ₁ =N and X ₂ =X ₃ =X ₄ =C or X ₂ =N and X ₁ = _X3 = _X4 =C or _X3 =N and X1 ₌ X2= _X4 =C or _X4 =N and X1 _{= X2} = _X3 =C _;

Wherein, Y is optionally selected from Br, I, OTf, OTs, OSO ₂ Ph;

Among them, n is arbitrarily taken from 0, 1, 2;

Wherein, catalyst D is a complex formed by metal palladium or metal copper/ligand;

Wherein, the metal palladium is divalent palladium or zero-valent palladium, including Pd(OAc) ₂ , Pd(OTf) ₂ , Pd(TFA) ₂ , PdCl ₂ , Na ₂ PdCl ₄ , Pd(dba) ₂ , Pd ₂ (dba ) ) ₃ , can be used in combination with phosphine ligands when needed, phosphine ligands include: PhPCy ₂ , t-Bu ₃ P, PCy ₃ , Ar ¹ P(Ar ² ) ₂ , dppe, dppp, dppb, dppf, Xphos, Sphos , Xantphos, wherein Ar ¹ and Ar ² are independent, optionally selected from phenyl, methoxy-substituted phenyl, methyl-substituted phenyl, furyl, thienyl; wherein the amount of metal palladium and the substance of the ligand The ratio is 1:1 to 1:3;

Wherein, the metal copper is a complex formed by divalent or monovalent copper and a ligand, wherein the amount ratio of the metal copper and the ligand is 1:1 to 1:3, wherein the metal copper includes Cu(Cl) _z , Cu(Br) _z , Cu(I) _z , Cu(OAc) _z , Cu(OTf) _z , wherein z=1 or 2; the ligand used is optionally selected from the following structures: 8-hydroxyquinoline, Alkyl-substituted 8-hydroxyquinoline, BINOL, 2,2'-biphenol, proline;

Wherein, the organic solvent is optionally selected from the following solvents or a combination of solvents: N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide, N-methylpyrrolidone; preferably dimethyl sulfoxide;

The base is optionally potassium tert-butoxide, potassium bis(trimethylsilyl)amide, K ₂ CO ₃ , Cs ₂ CO ₃ , Li ₂ CO ₃ , K ₃ PO ₄ , Li ₃ PO ₄ , Na ₃ PO _4. K ₂ HPO ₄ , KH ₂ PO ₄ ;

The material ratio of the catalyst D, the substrate enaminone E, and the base is 0.002:1:1 to 0.2:1:5;

Described reaction temperature is 40 to 200 degrees Celsius;

The separation and purification include but are not limited to column chromatography, recrystallization and distillation.

Preferably, catalyst D is Pd(OAc) ₂ without ligands.

Preferably, catalyst D is a 1:2 combination of CuI and 8-hydroxyquinoline species.

In a second aspect, a method for preparing a 2,3-disubstituted indole compound is provided, wherein the 2,3-disubstituted indole compound has the structure shown in E in equation (B), and the specific steps are the same as those described above. The preparation method of fused-ring [1,2-a]indole compounds is the same, except that the base in the scheme is replaced with LiOH, NaOH, KOH or CsOH, and the reaction process is shown in equation (B):

Equation (B):

wherein the ranges of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X ₁ , X ₂ , X ₃ , X ₄ , Y and n are the same as the above-mentioned fused rings [1,2-a]Indole compounds have the same range in the preparation method.

The synthetic method provided by the invention has the following advantages and beneficial effects:

1) The method is suitable for the synthesis of fused ring [1,2-a]indole compounds containing various substituents, the reaction operation is simple, the by-products are few, and the purification is easy;

2) The raw materials of the present invention are cheap and easy to obtain, and the use of ligand-free metal palladium or cheap metal copper as a catalyst effectively reduces the cost of the catalyst, provides a new route selection for the synthesis of active molecules containing this type of framework, and has good performance. Prospects for industrial application.

Detailed ways

The features and advantages of the present invention can be further understood from the following detailed description. The examples provided are merely illustrative of the methods of the present invention, and are not intended to limit the remainder of the present disclosure in any way.

Example 1

Using 3-(2-iodoaniline)-2-methylcyclohexenone as the standard substrate, the reaction conditions for the copper-catalyzed synthesis of fused-ring [1,2-a]indole compounds were studied:

Among them, the copper catalyst represents cuprous chloride, cuprous bromide and cuprous iodide, the ligand is the structure drawn in the table, the mol% refers to the relative molar amount, equiv represents the equivalent, the base represents the commonly used inorganic base, and the organic solvent is Anhydrous solvent in a volume of 2 mL. Among them, DMSO is dimethyl sulfoxide, DMF is N,N'-dimethylformamide, NR means no reaction, and ND means no target product is generated. a is the separation yield, and b is the NMR yield.

Example 2

Using 3-(2-iodoaniline)-2-methylcyclohexenone as the standard substrate, the reaction conditions for the synthesis of fused-ring [1,2-a]indoles catalyzed by palladium were studied:

Among them, the palladium catalyst represents Pd(PPh ₃ ) ₄ , Pd ₂ (dba) ₃ , Pd(OAc) ₂ , the ligand is the structure drawn in the table, mol% refers to the relative molar amount, equiv represents the equivalent, and the base represents the commonly used inorganic Base and organic base, the organic solvent is a common anhydrous solvent, and the volume is 1 mL. Where DMSO is dimethyl sulfoxide, DMF is N,N'-dimethylformamide, NMP is N-methylpyrrolidone NR, Dioxane is dioxane, DCE is 1,2-dichloroethane, dppe stands for 1,2-bis(diphenylphosphino)ethane, and NR stands for no reaction. a is the separation yield, b is the GC yield (internal standard is dodecane).

Example 3

Preparation of 10-methyl-7H-8,9-[1,2-a]indol-6-one (method 1)

The 10 mL reaction tube and the magnetic stirring bar were pre-dried, and then under the protection of argon, 0.2 mL of the DMSO solution of the metal copper complex (containing 0.002 mmol CuI and 0.004 mmol 8-hydroxyquinoline) was added to the reaction tube, 65.8 mg3-(2-iodoaniline)-2-methylcyclohexenone and 41.5mg K ₂ CO ₃ , then 1.8 mL of dimethyl sulfoxide solvent was added, and the whole reaction was placed on a heating block at 120°C, and TLC monitored the whole The reaction process, after the reaction was completed, cooled to room temperature, diluted with ethyl acetate, transferred to a 50 mL separatory funnel, washed once with water, separated, the aqueous phase was extracted three times with ethyl acetate, washed twice with water, and washed once with saturated brine, Dry over anhydrous sodium sulfate, filter, and then concentrate the filtrate. The obtained crude product uses petroleum ether and ethyl acetate mixed solution (10/1, v/v) as the eluent, and uses 300-400 mesh silica gel as the separation resin to carry out the column. Chromatographic isolation gave 10-methyl-7H-8,9-o[1,2-a]indol-6-one (white solid, 33.2 mg), yield: 83%. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.46-8.43 (m, 1H), 7.44-7.42 (m, 1H), 7.32-7.26 (m, 2H), 2.90 (t, J=6.2Hz, 2H), 2.77 (t, J=6.3 Hz, 2H), 2.18 (s, 3H), 2.11-2.04 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.4, 134.6, 133.3, 131.2, 124.3, 123.8, 117.9 , 116.4, 112.3, 34.6, 21.9, 21.3, 8.6.

Example 4

Preparation of 10-methyl-7H-8,9-[1,2-a]indol-6-one (method 2)

The 4mL reaction flask and the magnetic stirring bar were pre-dried, and under the protection of argon, 2.5mL metal palladium solution in DMSO (containing 0.0025mmol Pd(OAc) ₂ ), 163.4mg 3-(2-iodoaniline) were respectively added to the reaction tube )-2-methylcyclohexenone and 159.2mg K ₃ PO ₄ , then add 2.5mL dimethyl sulfoxide solvent, place the whole reaction on a heating module at 120°C, and monitor the whole reaction progress by TLC. Cooled to room temperature, diluted with ethyl acetate, transferred to a 50 mL separatory funnel, washed once with water, separated, the aqueous phase was extracted three times with ethyl acetate, washed twice with water, once with saturated brine, dried over anhydrous sodium sulfate, filtered , then the filtrate is concentrated, the obtained crude product is made of petroleum ether and ethyl acetate mixed solution (10/1, v/v) as eluent, and 300-400 mesh silica gel is used as separation resin to carry out column chromatography separation to obtain 10-methyl yl-7H-8,9-o[1,2-a]indol-6-one (white solid, 93.7 mg), yield: 94%.

Note: "Method 1" in the following examples refers to the completion according to the synthetic route of Example 3, except that the substrate enaminone F, which corresponds to the product, is changed; "Method 2" refers to the synthesis according to Example 4. The route is complete except that the substrate enaminone, which corresponds to the product, is changed.

Example 5

1,10-Dimethyl-7H-8,9-[1,2-a]indol-6-one

White solid, method 1: 30.6 mg, 72% yield; method 2: 68% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (d, J=8.2 Hz, 1H), 7.19-7.11 (m, 1H), 6.99 (d, J=7.4 Hz, 1H), 2.88 (t, J= 6.2Hz, 2H), 2.76 (t, J=6.4Hz, 2H), 2.67 (s, 3H), 2.36 (s, 3H), 2.13-2.01 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ169.3, 135.1, 133.0, 130.2, 129.3, 125.8, 124.2, 114.4, 113.2, 34.7, 21.8, 21.2, 20.3, 11.9.

Example 6

2,10-Dimethyl-7H-8,9-[1,2-a]indol-6-one

White solid, method 1: 34.9 mg, 82% yield; method 2: 90% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30 (d, J=8.3 Hz, 1H), 7.21 (s, 1H), 7.10 (d, J=8.3 Hz, 1H), 2.88 (t, J=6.2 Hz) , 2H), 2.79–2.68 (m, 2H), 2.46 (s, 3H), 2.15 (s, 3H), 2.12–2.00 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.2, 133.4, 133.3 , 132.7, 131.4, 125.4, 118.0, 116.0, 112.1, 34.5, 21.9, 21.7, 21.3, 8.6.

Example 7

3,10-Dimethyl-7H-8,9-[1,2-a]indol-6-one

White solid, method 1: 34.2 mg, 80% yield; method 2: 84% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (s, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.10 (d, J=7.9 Hz, 1H), 2.88 (t, J=6.2 Hz , 2H), 2.75(t, J=6.4Hz, 2H), 2.48(s, 3H), 2.16(s, 3H), 2.10-2.04(m, 2H); ¹³ C NMR (100MHz, CDCl ₃ )δ169. 4, 134.9, 134.3, 132.6, 129.0, 125.0, 117.5, 116.8, 112.2, 34.6, 21.93, 21.88, 21.3, 8.6.

Example 8

2,4,10-Trimethyl-7H-8,9-[1,2-a]indol-6-one

White solid, method 1: 33.6 mg, 74% yield; method 2: 82% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.03 (s, 1H), 6.91 (s, 1H), 2.89 (t, J=6.2 Hz, 2H), 2.77 (t, J=6.4 Hz, 2H), 2.60 (s,3H), 2.41(s,3H), 2.13(s,3H), 2.11–2.02(m,2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.6, 134.9, 133.8, 133.3, 132.6, 129.0, 126.4, 115.6, 112.4, 35.3, 23.1, 22.5, 21.3, 21.2, 8.7.

Example 9

2-Fluoro-10-methyl-7H-8,9-do[1,2-a]indol-6-one

White solid, method 1: 32.9 mg, 76% yield; method 2: 90% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (dd, J=8.9, 4.8 Hz, 1H), 7.06 (dd, J=8.9, 2.5 Hz, 1H), 6.98 (td, J=9.1, 2.6 Hz, 1H), 2.90(t, J=6.2Hz, 2H), 2.76(t, J=6.2Hz, 2H), 2.14(s, 3H), 2.12-2.06(m, 2H); ¹³ C NMR (100MHz, CDCl) ₃ ) δ169.1, 160.1 (d, J _C–F = 240.0Hz), 135.1, 132.5 (d, J _C–F = 9.5 Hz), 130.8, 117.3 (d, J _C–F = 9.0 Hz), 112.1 (d , J _C-F = 3.8Hz), 111.4 (d, J _C-F = 24.5Hz), 103.8 (d, J _C-F = 23.9Hz), 34.3, 21.9, 21.2, 8.5; ¹⁹ F NMR (376MHz, CDCl ₃ ) δ–119.06.

Example 10

2-Chloro-10-methyl-7H-8,9-do[1,2-a]indol-6-one

White solid, method 1: 35.4 mg, 76%, yield; method 2: 74%, yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (d, J=8.7 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.22 (dd, J=8.7, 2.1 Hz, 1H), 2.90 (t, J=6.2Hz, 2H), 2.76 (t, J=6.2Hz, 2H), 2.14 (s, 3H), 2.12–2.07 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169. 2, 134.8, 132.9, 132.6, 129.4, 124.2, 117.8, 117.3, 111.8, 34.4, 21.9, 21.2, 8.5.

Example 11

2-Bromo-10-methyl-7H-8,9-do[1,2-a]indol-6-one

White solid, method 1: 44.9 mg, 81% yield; method 2: 76% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (d, J=8.6 Hz, 1H), 7.53 (d, J=1.9 Hz, 1H), 7.36 (dd, J=8.7, 2.0 Hz, 1H), 2.90 (t, J=6.2Hz, 2H), 2.76 (t, J=6.4Hz, 2H), 2.14 (s, 3H), 2.12–2.07 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169. 3, 134.7, 133.3, 133.1, 126.9, 120.8, 117.8, 117.2, 111.7, 34.5, 21.9, 21.2, 8.5.

Example 12

10-Methyl-2-trifluoromethyl-7H-8,9-[1,2-a]indol-6-one

White solid, method 1: 44.9 mg, 81% yield; method 2: 70% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (d, J=8.6 Hz, 1H), 7.53 (d, J=1.9 Hz, 1H), 7.36 (dd, J=8.7, 2.0 Hz, 1H), 2.90 (t, J=6.2Hz, 2H), 2.76 (t, J=6.4Hz, 2H), 2.14 (s, 3H), 2.12–2.07 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169. 3, 134.7, 133.3, 133.1, 126.9, 120.8, 117.8, 117.2, 111.7, 34.5, 21.9, 21.2, 8.5; ¹⁹ FNMR (376 MHz, CDCl ₃ ) δ-61.03.

Example 13

10-Methyl-2-nitro-7H-8,9-[1,2-a]indol-6-one

Yellow solid, method one: 33.5 mg, 69% yield; method two: 72% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.50 (d, J=9.0 Hz, 1H), 8.30 (d, J=2.2 Hz, 1H), 8.14 (dd, J=9.0, 2.2 Hz, 1H), 2.96 (t, J=6.2Hz, 2H), 2.82 (t, J=6.4Hz, 2H), 2.23 (s, 3H), 2.19–2.08 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169. 5, 144.4, 137.7, 136.7, 131.4, 119.6, 116.4, 114.1, 112.8, 34.5, 21.9, 21.0, 8.5.

Example 14

5-Methyl-6H-7,8-[3,2-b]indolazin-9-one

Yellow solid, method one: 29.1 mg, 73% yield; method two: 52% yield. ¹ H NMR (400 MHz, C ₆ D ₆ ) δ 8.52 (dd, J=4.7, 1.6 Hz, 1H), 7.27 (dd, J=7.7, 1.6 Hz, 1H), 6.82 (dd, J=7.7, 4.7 Hz, 1H), 2.17 (t, J=6.4 Hz, 2H), 2.01 (t, J=6.2 Hz, 2H), 1.73 (s, 3H), 1.17–1.03 (m, 2H); ¹³ C NMR (100 MHz) , C ₆ D ₆ )δ166.1, 148.9, 144.5, 134.6, 125.2, 123.6, 119.0, 108.2, 35.0, 21.5, 20.6, 7.9.

Example 15

5-Methyl-6H-7,8-[4,3-b]indolazin-9-one (method 1)

Example 16

10-Methyl-7H-8,9-[3,4-b]indolazin-6-one (method 1)

Example 17

10-Methyl-7H-8,9-[2,3-b]indolazin-6-one (method 1)

Example 18

10-Benzyl-7H-8,9-[1,2-a]indol-6-one

White solid, method 1: 34.6 mg, 63% yield; method 2: 90% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.48 (d, J=8.1 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.32-7.16 (m, 7H), 4.03 (s, 2H) , 2.90 (t, J=6.4Hz, 2H), 2.77 (t, J=6.4Hz, 2H), 2.17–2.03 (m, 2H).

Example 19

10-Phenyl-7H-8,9-[1,2-a]indol-6-one

White solid, method 1: 27.4 mg, 52% yield; method 2: 67% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.57-8.54 (m, 1H), 7.61-7.59 (m, 1H), 7.51-7.49 (m, 4H), 7.36-7.19 (m, 3H), 3.07 (t , J=6.2Hz, 2H), 2.85 (t, J=6.2Hz, 2H), 2.12–2.06 (m, 2H).

Example 20

10-(4-Trifluoromethyl)-phenyl-7H-8,9-[1,2-a]indol-6-one

White solid, method 1: 40.6 mg, 62% yield; method 2: 63% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.56 (dd, J=7.6, 0.6 Hz, 1H), 7.75 (d, J=8.1 Hz, 2H), 7.61 (d, J=8.0 Hz, 2H), 7.56 (d, J=7.5Hz, 1H), 7.39–7.29 (m, 2H), 3.07 (t, J=6.3Hz, 2H), 2.87 (t, J=6.5Hz, 2H), 2.15–2.09 (m, 2H).

Example 21

10-(4-Methoxy)-phenyl-7H-8,9-[1,2-a]indol-6-one

White solid, method 1: 21.5 mg, 37% yield; method 2: 70% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.54 (d, J=8.1 Hz, 1H), 7.57 (d, J=7.4 Hz, 1H), 7.43-7.40 (m, 2H), 7.36-7.28 (m, 2H), 7.05–7.03 (m, 2H), 3.88 (s, 3H), 3.04 (t, J=6.2Hz, 2H), 2.84 (t, J=6.4Hz, 2H), 2.18–1.99 (m, 2H) ).

Example 22

10-n-Butyl-7H-8,9-[1,2-a]indol-6-one

White solid, method 1: 30.7 mg, 64% yield; method 2: 89% yield. ¹ H NMR (400MHz, CDCl ₃ )δ8.45-8.44(m,1H),7.45-7.44(m,1H),7.29-7.24(m,2H),2.89(t,J=6.4Hz,2H), 2.75(t,J=6.4Hz,2H),2.62(t,J=7.5Hz,2H),2.09-2.03(m,2H),1.63-1.55(m,2H),1.41-1.31(m,2H) , 0.92 (t, J=7.3 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.4, 134.7, 133.3, 130.6, 124.1, 123.7, 118.1, 117.2, 116.5, 34.6, 32.0, 23.7, 22.7, 22.0, 21.4, 14.1.

Example 23

10-Cyclohexylmethyl-7H-8,9-[1,2-a]indol-6-one

White solid, Method 2: 131.4 mg, 93% yield. ¹ H NMR (400MHz, CDCl ₃ )δ8.50-8.39(m,1H),7.47-7.39(m,1H),7.28-7.24(m,2H),2.89(t,J=6.2Hz,2H), 2.76 (t, J=6.4Hz, 2H), 2.50 (d, J=7.1Hz, 2H), 2.09–2.03 (m, 2H), 1.73–1.54 (m, 6H), 1.22–1.11 (m, 3H) , 1.03–0.93 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.4, 134.7, 134.0, 131.0, 124.1, 123.7, 118.4, 116.5, 116.1, 38.7, 34.6, 33.7, 32.0, 26.6, 26.4, 22.3 , 21.4.

Example 24

10-(2-Benzyloxy)ethyl-7H-8,9-[1,2-a]indol-6-one

White solid, Method 1: 26.6 mg, 42% yield: Method 2: 69% yield. ¹ H NMR (400 MHz, CDCl ₃ ) 8.48-8.46 (m, 1H), 7.47-7.45 (m, 1H), 7.35-7.25 (m, 7H), 4.51 (s, 2H), 3.69 (t, J=7.1 Hz, 2H), 2.98 (t, J=7.1 Hz, 2H), 2.93 (t, J=6.2 Hz, 2H), 2.77 (t, J=6.3 Hz, 2H), 2.10–2.02 (m, 2H).

Example 25

2-(6,7,8,9-Tetrahydropyrido[1,2-a]indol-6-one)-acetic acid tert-butyl ester

White solid, method one: 22.9 mg, 39% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.46-8.44 (m, 1H), 7.50-7.48 (m, 1H), 7.32-7.25 (m, 2H), 3.55 (s, 2H), 2.97 (t, J =7.5Hz, 2H), 2.79(t, J=7.5Hz, 2H), 2.12-2.09(m, 2H), 1.42(s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 170.2, 169.5, 135.4, 134.6, 130.0, 124.5, 124.0, 118.2, 116.5, 110.4, 34.5, 31.7, 28.2, 22.0, 21.2.

Example 26

9-Methyl-3H-1,2-dihydropyrrolo[1,2-a]indol-3-one

White solid, method 1: 23.0 mg, 62% yield; method 2: 30% yield. ¹ H NMR (400MHz, CDCl ₃ )δ8.02-8.05(m,1H),7.50-7.35(m,1H),7.30-7.26(m,2H),3.08(m,4H),2.19(s,3H) ); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 171.5, 139.2, 136.4, 130.4, 123.9, 123.3, 118.7, 113.7, 108.8, 35.1, 18.6, 8.4.

Example 27

11-Methyl-6H-7,8,9,10-tetrahydroazepino[1,2-a]indol-6-one (method 1)

Example 28

7,9-Dimethyl-2H-1hydro-pyrrolo[1,2-a]indol-3-one (method 1)

White solid: 28.9 mg, 73% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (d, J=8.0 Hz 1H), 7.22 (s, 1H), 7.09 (d, J=8.0 Hz 2H), 3.06 (s, 4H), 2.46 (s , 3H), 2.16(s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 171.4, 139.4, 136.6, 133.5, 128.6, 124.5, 118.7, 113.3, 108.6, 35.0, 21.9, 18.6, 8.4.

Example 29

10-(2-Phthalimide)-N-ethyl-7H-8,9-[1,2-a]indol-6-one (method 2)

Yellow solid: 42.5 mg, 59% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.42-8.39 (m, 1H), 7.82-7.80 (m, 2H), 7.70-7.68 (m, 2H), 7.60-7.58 (m, 1H), 7.26-7.23 (m, 2H), 3.90–3.86 (m, 2H), 3.02–3.00 (m, 2H), 2.98–2.92 (m, 2H), 2.74 (t, J=6.3Hz, 2H), 2.07–2.01 (m , 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.3, 168.2, 134.8, 134.6, 134.1, 132.0, 129.9, 124.4, 124.0, 123.3, 117.9, 116.4, 112.8, 37.3, 34.5, 23.2, 21.8, 21.2

Example 30

10-(3-Fluoro-4-cyano)phenyl-7H-8,9-[1,2-a]indol-6-one (method 2)

White solid: 32.2 mg, 53% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.56 (d, J=7.9 Hz, 1H), 7.76-7.72 (m, 1H), 7.56-7.54 (m, 1H), 7.42-7.31 (m, 4H), 3.07 (t, J=6.0 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 2.17-2.11 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.5, 163.4 (d, J _{C –F} = 257.7Hz), 141.4 (d, J _{C – F} = 8.6 Hz), 136.0, 134.9, 133.8, 128.1, 125.7 (d, J _{C – F} = 3.3 Hz), 125.4, 124.8, 118.2, 117.0, 116.96 (d, J _C-F = 19.7 Hz), 116.2 (d, J _C-F = 2.0 Hz), 114.2, 99.7 (d, J _C-F = 18.7 Hz), 34.6, 23.1, 21.3; ¹⁹ F NMR ( 376MHz, CDCl ₃ ) δ–105.87.

Example 31

10-Allyl-7H-8,9-[1,2-a]indol-6-one (method 1)

White solid: 34.0 mg, 75% yield. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.50-8.40 (m, 1H), 7.51-7.37 (m, 1H), 7.33-7.19 (m, 2H), 5.92 (ddt, J=16.2, 10.1, 6.1Hz ,1H),5.24–4.87(m,2H),3.38(d,J＝6.0Hz,2H),2.88(t,J＝6.3Hz,2H),2.75(t,J＝6.4Hz,2H),2.06 (p, J=6.4 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.4, 135.6, 134.7, 134.0, 130.3, 124.2, 123.8, 118.2, 116.4, 115.6, 114.2, 34.5, 28.3, 21.8, 21.2.

Example 32

1-Methyl-10-allyl-7H-8,9-[1,2-a]indol-6-one (method 1)

White solid: 33.5 mg, 70% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 (d, J=8.0 Hz, 1H), 7.23-7.08 (t, J=8.0 Hz, 4.0 Hz, 1H), 7.06-6.88 (d, J=4.0 Hz) ,1H),6.03(ddt,J＝17.1,10.2,5.2Hz,1H),5.05(dq,J＝10.2,1.8Hz,1H),4.89(dq,J＝17.1,1.9Hz,1H),3.53( dt, J=5.0, 1.9 Hz, 2H), 2.93–2.83 (m, 2H), 2.82–2.73 (m, 2H), 2.61 (s, 3H), 2.07 (m, 2H); ¹³ C NMR (100MHz, CDCl ₃ )δ169.4, 136.7, 135.2, 134.5, 129.9, 128.6, 126.1, 124.2, 115.5, 114.6, 114.3, 34.7, 29.3, 21.7, 21.2, 19.8.

Example 33

2-Methyl-10-allyl-7H-8,9-[1,2-a]indol-6-one (method 1)

White solid: 39.3 mg, 83% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (d, J=8.3 Hz, 1H), 7.24 (s, 1H), 7.11 (d, J=8.3 Hz, 1H), 5.95 (ddt, J=16.2, 10.1, 6.0Hz, 1H), 5.16–4.99 (m, 2H), 3.38 (d, J=6.0Hz, 2H), 2.88 (t, J=6.2Hz, 2H), 2.76 (t, J=6.3Hz, 2H), 2.45(s, 3H), 2.07(p, J=6.4Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.2, 135.6, 134.1, 133.3, 132.8, 130.5, 125.4, 118.3, 116.1, 115.6 , 114.0, 34.5, 28.2, 21.8, 21.7, 21.3.

Example 34

3-Methyl-10-allyl-7H-8,9-[1,2-a]indol-6-one (method 1)

White solid: 33.3 mg, 69% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (s, 1H), 7.33 (d, J=7.9 Hz, 1H), 7.09 (d, J=7.9 Hz, 1H), 5.93 (ddt, J=16.4, 10.8, 6.0Hz, 1H), 5.15–4.97 (m, 2H), 3.38 (d, J=5.9Hz, 2H), 2.88 (t, J=6.2Hz, 2H), 2.77 (t, J=6.3Hz, 2H), 2.48 (s, 3H), 2.07 (p, J=6.3 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.5, 135.7, 135.1, 134.3, 133.3, 128.1, 125.1, 117.9, 116.8, 115.6 , 114.1, 34.6, 28.4, 21.9, 21.9, 21.3.

Example 35

2-Fluoro-10-allyl-7H-8,9-[1,2-a]indol-6-one (method 1)

White solid: 37.6 mg, 77% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 (dd, J=8.9, 4.8 Hz, 1H), 7.09 (dd, J=8.9, 2.6 Hz, 1H), 6.98 (td, J=9.1, 2.6 Hz, 1H), 5.91 (ddt, J=17.5, 9.5, 6.0Hz, 1H), 5.19–4.98 (m, 2H), 3.35 (dt, J=6.2, 1.7Hz, 2H), 2.90 (t, J=6.2Hz , 2H), 2.77 (t, J=6.3Hz, 2H), 2.09 (p, J=6.4Hz, 2H). ¹³ C NMR (100MHz, CDCl ₃ )δ169.2, 160.0 (d, J _CF =238.5Hz), 135.8, 135.2, 131.6 (d, J _CF = 9.5Hz), 131.0, 117.4 (d, J _CF = 9.0 Hz), 116.0, 114.0 (d, J _CF = 3.8 Hz), 111.6 (d, J _CF = 24.5 Hz) ), 104.3 (d, J _CF =23.9 Hz), 34.4, 28.3, 21.9, 21.3; ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ-118.90.

Example 36

2-Chloro-10-allyl-7H-8,9-[1,2-a]indol-6-one (method 1)

White solid: 39.5 mg, 76% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36 (d, J=8.7 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.23 (dd, J=8.7, 2.1 Hz, 1H), 6.02 –5.78 (m, 1H), 5.15–5.00 (m, 2H), 3.36 (d, J=6.0Hz, 2H), 2.96–2.85 (m, 2H), 2.83–2.74 (m, 2H), 2.10 (p , J=6.4 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.3, 135.6, 135.1, 133.1, 131.8, 129.4, 124.3, 118.1, 117.4, 116.0, 113.7, 34.4, 28.2, 21.9, 21.2.

Example 37

2-Bromo-10-allyl-7H-8,9-[1,2-a]indol-6-one (method 1)

White solid: 46.3 mg, 76% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (d, J=8.7 Hz, 1H), 7.56 (d, J=1.8 Hz, 1H), 7.36 (dd, J=8.7, 1.9 Hz, 1H), 5.91 (ddt, J=17.3, 9.4, 6.0Hz, 1H), 5.17–4.95 (m, 2H), 3.35 (d, J=5.9Hz, 2H), 2.90 (t, J=6.3Hz, 2H), 2.78 ( t, J=6.4Hz, 2H), 2.09 (p, J=6.4Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.3, 135.5, 135.1, 133.4, 132.2, 127.0, 121.2, 117.8, 117.2, 116.1 , 113.6, 34.4, 28.2, 21.9, 21.2.

Example 38

2-Nitro-10-allyl-7H-8,9-[1,2-a]indol-6-one (method 1)

Yellow solid: 33.4 mg, 62% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.51 (d, J=9.0 Hz, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.13 (dd, J=9.0, 2.2 Hz, 1H), 5.93 (ddt, J=16.3, 10.4, 6.0Hz, 1H), 5.17–4.99 (m, 2H), 3.43 (d, J=5.9Hz, 2H), 2.96 (t, J=6.3Hz, 2H), 2.84 ( t, J=6.4Hz, 2H), 2.14 (p, J=6.4Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.5, 144.4, 137.8, 137.5, 134.7, 130.5, 119.6, 116.4, 116.4, 114.7 , 114.5, 34.4, 28.0, 21.9, 20.9.

Example 39

10-cinnamyl-7H-8,9-[1,2-a]indol-6-one (method 1)

Yellow oily liquid: 32.6 mg, 54% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.53-8.46 (m, 1H), 7.51 (dd, J=7.3, 1.6 Hz, 1H), 7.36-7.28 (m, J=14.1, 7.2, 4.4, 1.9 Hz ,6H),7.25–7.18(m,1H),6.51–6.42(m,1H),6.40–6.29(m,1H),3.59(dd,J=6.1,1.5Hz,2H),2.97(t,J = 6.3 Hz, 2H), 2.81 (t, J=6.4 Hz, 2H), 2.12 (p, J=6.4 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.5, 137.3, 134.8, 134.2, 130.7, 130.4, 128.6, 127.5, 127.3, 126.2, 124.4, 123.9, 118.3, 116.5, 114.4, 34.6, 27.6, 22.0, 21.3.

Example 40

10-(3-Methyl-2-butenyl)-7H-8,9-[1,2-a]indol-6-one (method 1)

White solid: 38.0 mg, 75% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.42-8.32 (m, 1H), 7.41-7.32 (m, 1H), 7.25-7.13 (m, 2H), 5.15 (dddd, J=7.0, 5.6, 2.8, 1.4Hz, 1H), 3.25 (d, J=7.0Hz, 2H), 2.91–2.78 (m, 2H), 2.76–2.62 (m, 2H), 2.00 (p, J=6.4Hz, 2H), 1.73 ( s, 3H), 1.67–1.59 (m, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.4, 134.8, 133.2, 132.3, 130.5, 124.2, 123.8, 122.0, 118.3, 116.5, 116.3, 34.6, 25.8, 23.1 , 21.9, 21.3, 18.1.

Examples 41-52:

The 10 mL reaction tube and the magnetic stirring bar were pre-dried, and then under the protection of argon, the DMSO solution of the metal copper complex (containing 0.02 mmol CuI and 0.04 mmol 8-hydroxyquinoline), enaminone was added to the reaction tube respectively. E and 20.7mg LiOH, then 1.8mL dimethyl sulfoxide solvent was added, the whole reaction was placed on a 120°C heating module, and the whole reaction progress was monitored by TLC. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate, and transferred to 50mL In the liquid funnel, washed once with water, separated, the aqueous phase was extracted with ethyl acetate three times, washed with water twice, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and then the filtrate was concentrated, and the obtained crude product was mixed with petroleum ether and mixed with water. Ethyl acetate mixture (5/1, v/v) was used as eluent, and 300-400 mesh silica gel was used as separation resin for column chromatography to obtain 2,3-disubstituted indole compounds G.

Example 41

4-(3-Methyl-1H-2-indole)butyric acid

White solid, 33.6 mg, 77% yield. ¹ H NMR (400MHz, DMSO-d ₆ )δ12.07(br,1H), 10.66(br,1H), 7.36(d,J=7.7Hz,1H), 7.23(d,J=8.0Hz,1H) ,6.98(m,1H),6.92(m,1H),2.70(t,J=7.4Hz,2H),2.21(t,J=7.4Hz,2H),2.15(s,3H),1.86(p, J=7.5 Hz, 2H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 174.3, 135.3, 134.9, 128.7, 120.1, 118.0, 117.5, 110.4, 105.2, 33.0, 24.8, 24.7, 8.3.

Example 42

4-(3,4-Dimethyl-1H-2-indole)butyric acid

White solid, 39.7 mg, 86% yield. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.08 (br, 1H), 10.59 (br, 1H), 7.03 (d, J=8.0Hz, 1H), 6.81 (t, J=7.5Hz, 1H) ,6.61(d,J＝7.0Hz,1H),2.66(t,J＝7.4Hz,2H),2.60(s,3H),2.33(s,3H),2.21(t,J＝7.4Hz,2H) , 1.82 (p, J=7.5Hz, 2H). ¹³ CNMR (100MHz, DMSO-d ₆ )δ174.4, 135.5, 134.5, 129.1, 127.0, 120.1, 119.6, 108.6, 106.0, 33.0, 24.8, 24.5, 20.0, 11.2 .

Example 43

4-(3,5-Dimethyl-1H-2-indole)butyric acid

White solid, 32.0 mg, 69% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.75 (br, 1H), 7.28 (s, 1H), 7.17 (d, J=8.2 Hz, 1H), 6.99-6.92 (m, 1H), 2.78 (t, J=7.2Hz, 2H), 2.46(s, 3H), 2.37(t, J=7.2Hz, 3H), 2.21(s, 3H), 1.97(p, J=7.2Hz, 2H); ¹³ C NMR( 100MHz, CDCl ₃ ) δ 179.6, 133.8, 133.7, 129.6, 128.3, 122.8, 118.1, 110.1, 107.2, 33.0, 25.2, 24.8, 21.6, 8.6.

Example 44

4-(3,6-Dimethyl-1H-2-indole)butyric acid

White solid, 35.7 mg, 77% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (br, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.07 (s, 1H), 6.93 (d, J=8.0 Hz, 1H), 2.78 (t,J=7.3Hz,2H),2.46(s,3H),2.38(t,J=7.2Hz,2H),2.22(s,3H),1.98(p,J=7.2Hz,2H); ¹³ C NMR (100 MHz, _CDCl3 ) δ 179.7, 135.8, 132.9, 131.1, 127.2, 120.8, 118.0, 110.5, 107.6, 33.0, 25.2, 24.8, 21.8, 8.7.

Example 45

4-(3-Methyl-5-fluoro-1H-2-indole)butyric acid

White solid, 30.6 mg, 65% yield. ¹ H NMR (400MHz, CD ₃ CN-d ₃ ) δ 8.99 (br, 1H), 7.22 (dd, J=8.7, 4.5Hz, 1H), 7.10 (dd, J=10.1, 2.6Hz, 1H), 6.82(m,1H),2.75(t,J=7.5Hz,2H),2.29(t,J=7.4Hz,2H),2.15(s,3H),1.93–1.87(m,2H) ^.13C NMR (100MHz, CD ₃ CN-d ₃ )δ174.8, 158.3 (d, J _C-F = 229.2 Hz), 138.0, 133.0, 130.4 (d, J _C-F = 9.6 Hz), 111.9 (d, J _C -F = 9.6 Hz) = 9.7Hz), 109.1 (d, J _C–F = 26.1 Hz), 107.6 (d, J _{C – F} = 4.5 Hz), 103.3 (d, J _{C – F} = 23.1 Hz), 33.3, 25.7, 25.4, 8.4; ¹⁹ F NMR (376 MHz, CD ₃ CN-d ₃ ) δ - 127.52.

Example 46

4-(3-Methyl-5-chloro-1H-2-indole)butyric acid

White solid, 32.1 mg, 64% yield. ¹ H NMR (400MHz, DMSO-d ₆ )δ12.09(br,1H), 10.90(br,1H), 7.39(d,J=2.0Hz,1H), 7.23(d,J=8.5Hz,1H) ,6.97(dd,J＝8.5,2.1Hz,1H),2.69(t,J＝7.5Hz,2H),2.20(t,J＝7.4Hz,2H),2.12(s,3H),1.84(p, J=7.4 Hz, 2H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 174.3, 137.1, 133.7, 129.9, 122.7, 119.9, 116.9, 111.9, 105.4, 32.9, 24.8, 24.5, 8.2.

Example 47

4-(3-Methyl-5-bromo-1H-2-indole)butyric acid

White solid, 40.2 mg, 68% yield. ¹ H NMR (400MHz, CD ₃ CN-d ₃ ) δ 9.09 (br, 1H), 7.60-7.55 (m, 1H), 7.20 (dd, J=8.5, 0.6Hz, 1H), 7.13 (dd, J =8.5,1.9Hz,1H),2.75(t,J=7.5Hz,2H),2.33–2.24(m,2H),2.15(s,3H),1.93–1.87(m,2H) ^.13C NMR( 100MHz, CD ₃ CN-d ₃ )δ175.0, 137.5, 135.1, 131.9, 123.9, 121.1, 113.0, 112.1, 107.2, 33.3, 25.5, 25.4, 8.4.

Example 48

4-(3-Methyl-5-nitro-1H-2-indole)butyric acid

Yellow solid, 36.5 mg, 70% yield. ¹ H NMR (400MHz, DMSO-d ₆ )δ12.11(br,1H),11.53(br,1H),8.37(d,J=2.2Hz,1H),7.92(dd,J=8.9,2.3Hz, 1H), 7.39 (d, J=8.9Hz, 1H), 2.75 (t, J=7.5Hz, 2H), 2.25-2.21 (m, 5H), 1.87 (p, J=7.4Hz, 2H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 174.2, 140.0, 139.3, 138.7, 128.1, 115.9, 114.7, 110.8, 108.5, 32.9, 24.8, 24.3, 8.1.

Example 49

3-(3-Methyl-1H-2-indole)propionic acid

White solid, 23.2 mg, 57% yield. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.12(br, 1H), 7.55-7.47(m, 1H), 7.28(d, J=7.7Hz, 1H), 7.18-7.07(m, 2H), 3.05( t, J=6.7Hz, 2H), 2.74 (t, J=6.8Hz, 2H), 2.25 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 179.1, 135.3, 133.2, 129.1, 121.6, 119.2, 118.4, 110.6, 107.6, 34.0, 20.8, 8.6.

Example 50

5-(3-Methyl-1H-2-indole)pentanoic acid

Example 51

White solid, 32.4 mg, 67% yield. ¹ H NMR (400 MHz, CD ₃ CN-d ₃ ) δ 9.02 (br, 1H), 7.43 (dt, J=7.8, 1.0 Hz, 1H), 7.28 (dt, J=8.0, 0.9 Hz, 1H), 7.04(ddd,J=8.1,7.1,1.3Hz,1H),6.98(ddd,J=8.1,7.0,1.1Hz,1H),5.97(ddt,J=17.2,10.1,6.2Hz,1H),5.11– 4.88(m, 2H), 4.38(br, 1H), 3.43(dt, J=6.2, .7Hz, 2H), 2.81–2.70(m, 2H), 2.29(t, J=7.4Hz, 3H), 1.92 -1.86(m, 2H). ¹³ C NMR (100MHz, CD ₃ CN-d ₃ )δ174.7, 139.0, 136.5, 136.2, 129.3, 121.6, 119.4, 118.9, 114.5, 111.3, 109.5, 33.4, 29.0, 25.7, 25.6 .

Example 52

4-(3-Phenyl-1H-2-indole)butyric acid

White solid, 21.5 mg, 39% yield. ¹ H NMR (400MHz, CD ₃ CN-d ₃ ) δ 9.35 (br, 1H), 7.51 (dd, J=8.0, 1.0 Hz, 1H), 7.50-7.40 (m, 4H), 7.36 (dt, J ＝8.0,0.9Hz,1H),7.32–7.25(m,1H),7.11(ddd,J＝8.2,7.0,1.2Hz,1H),7.02(ddd,J＝8.0,7.0,1.1Hz,1H), 4.37(br, 1H), 2.92–2.82(m, 2H), 2.27(t, J=7.3Hz, 2H), 1.92(dt, J=4.9, 2.4Hz, 2H). ¹³ C NMR (100MHz, CD ₃ CN-d ₃ )δ174.7, 136.6, 136.4, 130.3, 129.5, 128.3, 126.7, 122.2, 120.4, 119.1, 114.5, 111.7, 33.5, 26.2, 25.6.

The above-mentioned embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above-mentioned embodiments, and any other changes, modifications, substitutions, combinations, The simplification should be equivalent replacement manners, which are all included in the protection scope of the present invention.

Claims (5)

1. A preparation method of a fused ring [1,2-a] indole compound, the fused ring [1,2-a] indole compound has the structure shown in F in equation (A), wherein It is characterized in that the specific steps are: In an organic solvent, catalyst D, substrate enaminone E and base are added to react at room temperature, and after separation and purification, a condensed ring [1,2-a]indole compound is obtained. The reaction process is as shown in equation (A) shown: Equation (A):

Described raw material enaminone E has the structure shown in E in equation (A); Wherein, R ¹ is alkyl, cycloalkyl, heteroatom-containing alkyl, aryl, heteroaryl or fluorine; R ² , R ³ , R ⁴ , R ⁵ are independent, optionally from the following structures: hydrogen Atom, alkyl, cycloalkyl, heteroatom-containing alkyl, fluorine, chlorine; nitro; alkyl or aryl substituted oxygen; wherein, R ⁶ , R ⁷ , R ⁸ and R ⁹ are selected from hydrogen atoms; Wherein, X ₁ , X ₂ , X ₃ , and X ₄ are optionally selected from C or N, and are one of the following combinations: X ₁ =N and X ₂ =X ₃ =X ₄ =C or X ₂ =N and X ₁ = _X3 = _X4 =C or _X3 =N and X1 ₌ X2= _X4 =C or _X4 =N and X1 _{= X2} = _X3 =C _; Wherein, Y is optionally selected from Br, I, OTf, OTs, OSO ₂ Ph; Among them, n is arbitrarily taken from 0, 1, 2; Wherein, catalyst D is a complex formed by metal palladium or metal copper/ligand; Wherein, the metal palladium is divalent palladium or zero-valent palladium, selected from Pd(OAc) ₂ , Pd(OTf) ₂ , Pd(TFA) ₂ , PdCl ₂ , Na ₂ PdCl ₄ , Pd(dba) ₂ , Pd ₂ ( dba) ₃ , which can be used in combination with a phosphine ligand selected from: PhPCy ₂ , t-Bu ₃ P, PCy ₃ , Ar ¹ P(Ar ² ) ₂ , dppe, dppp, dppb, dppf, Xphos , Sphos, Xantphos, wherein Ar ¹ and Ar ² are independent, optionally selected from phenyl, methoxy-substituted phenyl, methyl-substituted phenyl, furyl, thienyl; wherein metal palladium and ligand The ratio of the amount is 1:1 to 1:3; Wherein, the metal copper is a complex formed by monovalent copper and a ligand, wherein the ratio of the amount of the metal copper and the ligand is 1:1 to 1:3, wherein the metal copper is selected from Cu(Cl) _z , Cu(Br) _z , Cu(I) _z , Cu(OAc) _z , Cu(OTf) _z , where z=1; the ligands used are optionally selected from the following structures: 8-hydroxyquinoline, alkyl substituted 8-hydroxyquinoline, BINOL, 2,2'-biphenol, proline; Wherein, the organic solvent is optionally selected from the following solvents or a combination of solvents: N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone; _The base is optionally selected from potassium tert _- butoxide, potassium bis ₍ trimethylsilyl ₎ amide, _K2CO3 , _Cs2CO3 , _Li2CO3 , _K3PO4 , _{Li3PO4 , Na3PO 4.} K ₂ HPO ₄ , KH ₂ PO ₄ ; The material ratio of the catalyst D, the substrate enaminone E, and the base is 0.002:1:1 to 0.2:1:5; Described reaction temperature is 40 to 200 degrees Celsius; The separation and purification are selected from column chromatography, recrystallization and distillation. 2 . The method for preparing fused ring [1,2-a]indole compounds according to claim 1 , wherein the catalyst D is Pd(OAc) ₂ without a ligand. 3 . 3. the preparation method of fused ring [1,2-a] indole compound according to claim 1, is characterized in that, described catalyst D is the ratio 1 of the amount of substance of CuI and 8-hydroxyquinoline : 2 combinations. 4 . The method for preparing fused ring [1,2-a]indole compounds according to claim 1 , wherein the organic solvent is dimethyl sulfoxide. 5 . 5. a preparation method of a 2,3-disubstituted indole compound, the 2,3-disubstituted indole compound has the structure shown in G in equation (B), it is characterized in that, concrete steps and rights The preparation method of the fused ring [1,2-a]indole compound described in claim 1 is the same, except that the base in claim 1 is replaced with LiOH, NaOH, KOH or CsOH, and the reaction process is shown in equation (B) : Equation (B):

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X ₁ , X ₂ , X ₃ , X ₄ , Y and n are within the scope of claim 1 The scope of the preparation method of the fused ring [1,2-a]indole compounds described above is the same.